At autopsy, 50 percent of men aged 51-60 have histologic criteria for benign prostatic hyperplasia (BPH), and this incidence increases with age. This high incidence of BPH translates into about 300,000 surgical procedures per year at a cost of over one billion dollars annually. In spite of the high cost in disability and dollars, our initimate, detailed knowledge of the causes of BPH remains inadequate. Studies of androgens, the most intensively examined group of substances in the control of prostatic growth, and estrogens have failed to explain the definitive events leading to BPH. It long has been known that the presence of testis and aging are necessary for BPH to occur. However, it is most puzzling that as the frequency of BPH goes up with age, the most important acknowledged physiologic stiumlus to prostatic growth, testosterone, falls in plasma and the concentration of its binding protein, sex hormone- binding globulin (SHBG), rises. Further, within the prostate, testosterone does not rise with age in either stroma or epithelium, while dihydrotestosteron (DHT) is constant with age in stroma and falls substantially in epithelium. Recent observations may explain these inconsistencies and open new areas of understanding and therapy. Androgens and estrogens exert their effects through intracellular receptors. Attempts to unravel the role of androgens and estrogens in BPH rely on this well-established model as a basis from which to go forward. It has been demonstrated that the prostate contains an additional signaling system for androgens and estrogens that functions through the intermediacy of a receptor (RSHBG) for plasma SHBG. Using this signalling pathway, these steroids engender rapid rises in intracellular cAMP. We have shown that the system is involved in both growth and the nonligand activation of the androgen receptor. Others have shown that cAMP is a powerful modulator of the transciptional effects of endogen and estrogen receptors; however, virtually nothing is known of how cAMP-induced modulation or transcription is physiologically regulated. The RSHBG system is an ideal candidate to be such a regulator. Our long term objective is to integrate this new steroid signaling system into the general mechanisms of steroid hormone action in the prostate. Our specific aims in this applicatin include: unraveling the mechanism of RSHBG-induced activation of PSA secretion in the absence of androgens, examination of the mechanisms of RSHBG modulation of estrogen and androgen- induced gene transcription, and determination of the relationships among RSHBG, cAMP response element-dependent gene transcription and prostate growth.